Mario L. Rocci

The Pharmacokinetics and Pharmacodynamics of Newer Inotropic Agents

SummaryIn the past few years an intense effort has been directed toward the development of new inotropic agents for the treatment of chronic cardiac failure. Traditionally, therapy of this disease has included treatment with digitalis glycosides, diuretics, sodium restriction and vasodilators. While digitalis has proven to be an effective inotropic agent, it possesses a low therapeutic index and many patients remain symptomatic or ‘refractory’ despite its inotropic effects. This review focuses on the pharmacokinetics and pharmacodynamics of newer inotropic agents that have been developed or which are currently undergoing investigation.Amrinone and milrinone are two bipyridine derivatives which have been shown to be effective in the short term treatment of cardiac failure. Milrinone is currently being evaluated for its long term efficacy. The mechanism of action of amrinone and milrinone appears to be unrelated to the cardiac glycosides and sympathomimetic agents, and they are rapidly and well absorbed following oral administration. The bioavailability of milrinone appears to be somewhat reduced in patients with chronic cardiac failure. The distribution of these drugs to extravascular tissues is very rapid; the volume of distribution suggests that they are not extensively bound to tissues. While the volume of distribution of amrinone appears to be unaffected by the presence of heart failure, that of milrinone appears to be somewhat enhanced. The major route of elimination of both drugs appears to be excretion into urine as unchanged drug. A substantial fraction of the amrinone dose, however, undergoes hepatic metabolism to many metabolites, including an N-acetyl derivative. Clearance of amrinone and milrinone is dramatically reduced in patients with chronic cardiac failure compared with normal volunteers, resulting in proportionate increases in the serum half-lives of these drugs. Studies examining the acute and chronic disposition of these agents in cardiac failure patients have not demonstrated changes in their pharmacokinetics secondary to improvements in cardiocirculatory function. Both drugs show strong correlations between mean improvements in haemodynamics and drug serum concentrations, although considerable intrapatient variability may exist. It is currently unclear as to whether the site for the pharmacological action of amrinone is pharmacokinetically distinguishable from plasma.Enoximone and its sulphoxide metabolite, piroximone, are two compounds currently undergoing investigation for the treatment of chronic cardiac failure. Like the bipyridine derivatives, the mechanism of action of these compounds appears to be unrelated to sodium-potassium ATPase inhibition or sympathomimetic activity. Following oral administration of enoximone a substantial fraction of the dose is converted to piroximone on the first pass through the liver. The volumes of distribution of enoximone and piroximone do not suggest extensive tissue distribution of these drugs. The major pathway for elimination of enoximone is conversion to piroximone with subsequent renal excretion. Discrepancies exist in the literature concerning the half-life of these drugs. This discrepancy may be explained by the existence of terminal phases of disposition which have only recently been recognised. Any relationships between the haemodynamic effects of these drugs and their serum concentrations remain to be determined.Dobutamine, a synthetic catecholamine, was the first inotropic agent to become available for therapeutic use after the advent of digoxin. The limited data examining dobutamine pharmacokinetics suggest that it possesses an extremely high clearance, a limited volume of distribution, and a very short half-life. Strong relationships exist between changes in mean haemodynamic parameters and mean plasma dobutamine concentrations.Ibopamine, the 3,4- di-isobutyryl ester derivative of deoxyadrenaline (deoxyepinephrine; epinine) is an orally active, positive inotropic drug with dopaminergic vasodilatory activity. Upon oral administration, deoxyadrenaline exists primarily in the conjugated state in plasma. Elimination of this drug is primarily through metabolism; homovanillic acid is the primary urinary metabolite. The time course of haemodynamic effects of ibopamine greatly exceed the plasma persistence of free deoxyadrenaline. The site of action of ibopamine may be in a physiological compartment which is pharmacokinetically distinguishable from plasma.The development and investigation of newer inotropic agents in the treatment of chronic cardiac failure is evolving. Many more studies are needed to fully elucidate the pharmacokinetics of these and future compounds, as well as the relationships between the pharmacokinetics of these drugs and their effects in patients.

Milrinone in the treatment of chronic cardiac failure: a controlled trial

This study examines the acute hemodynamic response to intravenous and oral milrinone in 12 patients with moderate to moderately severe heart failure. The patients received milrinone or placebo at random in an 8-week double-blind trial. Dosing level and schedule were determined by the hemodynamic results. Acute and chronic plasma samples for milrinone concentration were drawn from patients throughout the study. Milrinone was administered intravenously in successive doses of 25, 50, and 75 micrograms/kg. This resulted in a 16.5%, 12.5%, and 28.4% peak increase in cardiac index, with a concomitant 24%, 29%, and 38% decrease in pulmonary capillary wedge pressure. There were no significant relationships between any of the mean maximal hemodynamic values and milrinone plasma concentration. Six patients received milrinone and six patients received placebo; only five patients completed the blinded phase. There was no significant difference between the groups in exercise capacity, but the conditions of five of the six patients who received placebo deteriorated. In two of the patients who received milrinone the aerobic capacity improved greater than 2 cc/min/kg over baseline, and an additional two patients reported a marked subjective improvement. The results of this study indicate that oral milrinone in the management of patients with chronic cardiac failure would justify larger controlled studies.

Immediate-Release and Sustained-Release Procainamide: Bioavailability at Steady State in Cardiac Patients

Excerpt Procainamide is effective in the prevention or treatment of various cardiac arrhythmias. Maintaining serum procainamide concentrations in the therapeutic range has been identified as an imp...

Combined Phenytoin and Phenobarbital Overdose

A 32-year-old female attempted suicide by consuming large quantities of both phenytoin (P) and phenobarbital (Pb). On hospital admission, serum drug concentrations (SDC), measured by immunoassay, were 46 μg/ml for P and 86 μg/ml for Pb. The patient remained unconscious, requiring mechanical ventilation, for the next two weeks. Serial SDC demonstrated: (1) continued P absorption over the next five days; (2) different elimination patterns for the two drugs (Pb exhibited first-order elimination while P elimination represented Michaelis-Menten kinetics); and (3) the limited effectiveness of forced alkaline diuresis in lowering Pb serum concentration, though resulting in an episode of pulmonary edema. The patients clinical status subsequently improved and correlated well with SDC decline into the usual therapeutic range.

Interpretation of serum phenytoin concentrations in uremia is assay‐dependent

A 25-year-old man with sickle cell disease and chronic renal insufficiency had tonic-clonic seizures treated with phenytoin. Serum phenytoin concentrations, total and free, measured by two homogenous enzyme immunoassays (EMIT®, ACA®) were reported to be within the therapeutic range, yet the patient experienced seizures. Values on discharge exceeded the therapeutic range but were not associated with signs or symptoms of toxicity. Reanalysis of serum samples by a more specific, high performance liquid chromatographic (HPLC) method revealed the previous values were spurious, apparently due to phenytoin metabolite cross-reactivity. Values by fluorescence polarization immunoassay (TDX®,) correlated well with those by HPLC, as well as with the patients clinical course.

Effects of Age on the Elimination of Labetalol

SummaryLabetalol is an α1- and β-adrenergic antagonist currently used in the treatment of hypertension. Studies which have evaluated the effects of age on its pharmacokinetics have yielded conflicting results. The purpose of this study is to comprehensively re-evaluate the effect of age on the elimination of labetalol. Data were obtained from 4 single-dose and 3 multiple-dose studies of the pharmacokinetics of the drug. An analysis of covariance was performed on the single-dose data to determine whether the type of subject evaluated (normotensive vs hypertensive), type of assay methodology used and/or age were significant factors affecting labetalol clearance estimates. A similar covariance procedure was used for the multiple-dose data, to assess whether the type of subject, duration of treatment and/or age were significant variables affecting labetalol elimination. Subsequent to the analysis of covariance, linear regression and correlation analysis was used to evaluate the effects of age on labetalol clearance.A modest though significant relationship was observed between the apparent oral clearance of the drug and age; it appeared slightly stronger when clearance was normalised for bodyweight. No relationship was found following multiple doses of the drug. Hence, age does not appear to be a significant factor affecting the oral clearance of labetalol, particularly in individuals receiving the drug in the long term.

The Effect of Single Doses of Cimetidine on Estimated Hepatic Blood Flow

Controversy exists as to whether H2-receptor antagonists decrease hepatic blood flow. This study examined the effect of single doses of cimetidine 300 and 600 mg po on apparent hepatic blood flow as estimated by indocyanine green (ICG) clearance. A double-blind, repeated-measure study was performed in nine supine healthy men. Following an overnight fast, placebo or cimetidine was administered one hour prior to ICG 0.5 mg/kg iv. Plasma samples were obtained serially for a period of 20 minutes following dye administration and stored at −70° until high performance liquid chromatographic analysis. Cimetidine had no apparent effect on mean ± SD ICG clearance following placebo, cimetidine 300 mg, and cimetidine 600 mg (366 ± 66 vs. 336 ± 55 vs. 350 ± 58 ml/min/m2, respectively; NS). Corresponding values for estimated hepatic blood flow were 632 ± 109, 580 ± 103, and 617 ± 112 ml/min, respectively; NS. No statistically significant changes in ICG half-life or volume of distribution at steady state occurred as a function of treatment. Contrary to previous reports, single-dose cimetidine administration appeared to have no appreciable effect on hepatic blood flow. These results implicate cimetidine binding to the cytochrome P-450 system as the sole mechanism responsible for inhibition of the systemic clearance of co-administered drugs metabolized by the liver.

Disposition of Intravenous and Intraperitoneal Cefoxitin During Chronic Intermittent Peritoneal Dialysis

The disposition of intravenous and intraperitoneal administered cefoxitin was evaluated in four males undergoing intermittent peritoneal dialysis. Each patient received 1 g of cefoxitin intravenously prior to an eight-hour dialysis; subsequently, one patient received another 1 g intravenous dose prior to an 18-hour dialysis while each of the other three patients had 100 mg of cefoxitin added to their eight hourly exchanges of dialysis fluid with 2 L per exchange. Serial blood, dialysate, and urine samples were collected and analyzed for cefoxitin by a microbiologic assay. Twenty-four hours after intravenous administration, serum cefoxitin concentrations were greater than 16 micrograms/mL (therapeutic breakpoint) in each patient. Mean cefoxitin dialysate concentrations averaged 7.8 +/- 3.8 micrograms/mL and were greater than 16 micrograms/mL in only 2 of 43 exchanges. After intraperitoneal administration, serum cefoxitin concentrations were highest after the eighth exchange (range 5.6 to 10.6 micrograms/mL). Thus, diffusion of cefoxitin across the placental membrane was not extensive. Dialysis removed only 10% to 20% of the intravenous dose.